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Year 2 - T2 Theme 1 > L20 Hormonal drug delivery > Flashcards

L20 Hormonal drug delivery Flashcards

1
Q

Why do we have dosage forms

A
  • Drug often in powder form
  • Tiny doses of drug (mg or mcg quantities)
  • Bulk up with excipients (such as water, lactose)
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2
Q

Why do we have different dosage forms?

A
  • Different clinical conditions
  • Different types of patient
  • Different routes of administration
  • Different physicochemical properties of drug
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3
Q

Factors to consider when designing dosage forms

A
  • Drug factors (solubility, partition coefficient, pKa, stability, MWt)
  • Biopharmaceutical factors (absorption, bioavailability, route of administration)
  • Therapeutic factors - disease, patient, route, local vs systemic delivery
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4
Q

Types of hormones

A
  • Modified amino acid derivatives
  • Peptide and proteins
  • Steroids
  • Eicosanoids
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5
Q

What are modified amino acid derivatives derived from

A
  • Derived from tyrosine and tryptophan
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6
Q

Examples of modified amino acid derivatives

A
  • Dopamine, thyroxine
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7
Q

What are peptides and proteins derived from

A
  • Derived from amino acids
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8
Q

Examples of peptides and proteins

A
  • Neuropeptides (vasopressin), pituitary hormones(gonadotropins), GI hormones (insulin)
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9
Q

What are steroids derived from

A
  • Cholesterol
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10
Q

Examples of steroids

A
  • Sex hormones (testosterone)

- Corticosteroids (hydrocortisone)

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11
Q

What are eicosanoids derived from

A
  • Derived from lipids
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12
Q

Examples of eicosanoids

A
  • Prostaglandins, leukotrienes
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13
Q

Main feature of modified amino acid derivatives

A
  • Generally orally active
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14
Q

Main features of peptide and proteins

A
  • Vary considerably in size from 3 amino acids to large, multisubunits glycoproteins
  • Susceptible to enzymatic degradation in GIT
  • Low absorption
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15
Q

Main features of steroids

A

eg. sex hormones
- Variable absorption
- Susceptible to extensive first pass hepatic metabolism
- Orally active BUT systemic Side effects

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16
Q

Give examples of when you might not want systemic delivery of a drug

A

Might not want systemic delivery of a drug if:

  • Side effects eg. corticosteroids
  • Bioavailability is low eg. peptide hormones, sex hormones
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17
Q

Examples of excipients

A
  • Diluents/fillers eg. lactose, water
  • Surfactants eg. polysorbates
  • Lubricants eg. Mg sterate
  • Disintegrants eg. starch
  • Viscosity enhancing agents eg cellulose derivatives
  • Flavours, colours, perfumes
  • Sweetening agents
  • Preservatives
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18
Q

Features of local delivery

A
  • Site of administration = site of action
  • Rapid onset of action
  • Less drug required
  • Absorption into the blood stream is not required
  • Absorption into the blood stream can lead to unwanted side effects
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19
Q

Why might corticosteroids be administered locally via different dosage forms

A

To avoid systemic side effects, need many different dosage forms

Intra-articular injections cortisone - tennis elbow
Creams and ointments betamethasone - eczema
Inhalers e.g. beclomethasone for asthma
Eye drops dexamethasone for inflammatory conditions of eye
Suppositories hydrocortisone inflammatory conditions of rectum

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20
Q

Factors to consider when administering modified amino acid derivatives and corticosteroids

A

Drug factors - low dose required

Biopharmaceutical factors - which route? orally bioavailable

Therapeutic factors - local vs systemic delivery

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21
Q

Factors to consider when administering peptide hormones eg insulin

A

Drug factors - peptide hormone, large molecule MW - 5800 Da

Biopharmaceutical factors - not absorbed after oral administration

Therapeutic factors - need systemic action, aim to mimic insulin secretion by normal pancreas - basal and bolus

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22
Q

Why are peptide hormones not absorbed after oral administration

A
  • Not absorbed after oral administration because of enzymatic degradation in lumen of GIT
  • Any that survives can’t readily cross GI epithelium into blood because too large
23
Q

How are insulins characterised

A

Insulins characterised by differences in:

Onset - how quickly they act
Peak - how quickly they achieve max impact
Duration - how long they last
Route of delivery - subcutaneous, inhaled

24
Q

When are rapid-acting insulins used

A
  • Rapid-acting insulins are used in insulin pumps, also known as continuous subcutaneous insulin infusion (CSII) devices
  • When delivered through a CSII pump, the rapid-acting insulins provide the basal insulin replacement, as well as the mealtime and high blood sugar correction insulin replacement
25
Q

Advantages of pulmonary route - systemic delivery

A
  • Large surface area (80-140 m2)
  • Thin epithelial barrier (0.1-0.2 um)
  • Good blood supply (100% cardiac output)
  • Avoids harsh environment of GI tract
  • Avoids first-pass hepatic metabolism
26
Q

When is rapid-acting inhaled insulin taken

A
  • Taken at the beginning of each meal
27
Q

What is inhaled insulin taken in combination

A
  • Used in combination with a long-acting injected insulin
28
Q

Factors to consider when administering sex hormones

A

Drug factors - steroid, lipophilic, MW - 270 Da

Biopharmaceutical factors - variable absorption after oral administration, extensive first pass hepatic metabolism, short t1/2

Therapeutic factors - systemic delivery required but try to avoid oral route. Either cyclical or continuous administration required

29
Q

Why do we need alternatives to oral route of administration

A
  • To increase bioavailability

- To offer sustained release

30
Q

Alternative routes of administration to the oral route

A
  • Parenteral route - IM injection, implant
  • Transdermal route - patch or gel
  • Intranasal route - spray
  • Buccal route - mucoadhesive system
  • Vagina - gel
31
Q

Features of IM injections

A

Oily injections - sustained release

  • Testosterone enantate (caster oil)
  • Testosterone decanoate, isocaprate, phenylproprionate and proprionate, undecanoate

Implants - sustained release
- Nexplanon (progestogen-nly contraception)

32
Q

Features of oily injections - IM injection

A
  • Sustained action because of lower rate of partition from oily vehicle into aqueous environment of tissue
  • Ester form of testosterone - DEPOT preparation - every 2-3 weeks
  • Requires esterases at injection site to cleave active drug from ‘pro’ drug
33
Q

Effects of ester at position 17

A
  • Decreases water solubility
  • Increases oil solubility
  • Deactivates molecule - can’t bind to androgen receptor
  • Ester cleaved/hydrolysed in blood - restores-OH so can attach to receptor
34
Q

How does release of steroid molecules from oily depots of long-chain esters in muscle tissue occur

A
  • Oil has some affinity for water and thus allows penetration of water; the ester is hydrolysed at the surface of the droplet
35
Q

Effect of total surface area of the droplet on the pharmokinetics of the drug

A
  • The total surface area of the droplet can influence release rate and hence pharmokinetics of the drug

Droplet dimenions and total surface area influenced by:
force of injection
viscosity and surface tension of oil phase
size of needle
environment into which it’s injected – exercise can increase plasma levels by increasing surface area of droplet.

36
Q

What is an etonogestrel(nexplanon) implant

A

The etonogestrel implant is a single-rod progestin contraceptive placed subdermally in the inner upper arm for long-acting reversible contraception in women

37
Q

How is etonogestrel implant delivered

A
  • Sub dermal implantation
  • Provides effective contraception for up to 3 years unless BMI greater than 35 kg/m2 in which case, may not provide effective contraception in 3rd year
38
Q

Advantages of intranasal administration - systemic

A
  • Large surface area (-180cm2)
  • Highly vascularised
  • Avoids first pass hepatic metabolism
  • Good bioavailability for low MW compounds

Product on the market - desmopressin

39
Q

Disadvantages of intranasal administration - systemic

A
  • Mucociliary clearance
  • Metabolic activity
  • Poor bioavailability for high MW compounds
40
Q

Features of buccal administration - systemic

A

Mucoadhesive testosterone buccal delivery system:

  • Applied twice daily
  • Adheres to gum or inner cheek
  • Sustained release of testosterone through buccal mucosa
  • Eating, tooth brushing, mouthwashing, chewing gum and alcoholic beverages have no significant effect on use and absorption from device
41
Q

How does the mucoadhesive testosterone buccal delivery system work

A
  • When applied the device begins to hydrate and testosterone is absorbed through the gum and inner cheek surfaces that are in contact with it.
  • Venous drainage from mouth is to superior vena cava, therefore avoids first-pass hepatic metabolism.
42
Q

Physiologic levels of testosterone

A

300 - 1050 ng/dL

43
Q

Changes in serum testosterone levels after buccal administration - systemic

A
  • Following initial application, serum testosterone rises to a max within 10-12 hours
  • Steady state levels are usually obtained after first two systems are applied
  • When removed and not reapplied, serum testosterone levels fall to below normal range in 2-4 hours
44
Q

Features of vaginal administration - systemic

A
  • Self-insertion and removal
  • Continuous release
  • Good patient compliance

Bioadhesive vaginal gel (crinone) progesterone released over 25-50 h

45
Q

What is crinone

A
  • Micronised progesterone and polymer polycarbophil in an oil in water emulsion system
  • Polymer, which is insoluble in water, swells within the vagina and forms a bioadhesive gel coating on the walls of the vagina. This allows progesterone to be absorbed through the vaginal tissue over 25 – 50 hours.
    Product used to assist reproduction.
46
Q

Vaginal administration (local) - device

A
  • Vaginal ring (estring)

- Estradiol released over 90 days

47
Q

What is an estring used for

A
  • Treatment of urogenital symptoms associated with postmenopausal atrophy of the vagina
48
Q

Example of vaginal administration (local) - pessary

A
  • Estradiol 10 mcg vaginal tablets (inserts) (vagifem)
49
Q

What is mirena

A
  • intrauterine device (IUD) with progestogen, sold under the brand name Mirena among others, is a intrauterine device that releases the hormone levonorgestrel
50
Q

What type of contraception does progestasert (mirena) provide

A
  • Progestasert (mirena) provides local rather than systemic contraception
  • May inhibit sperm survival and/or alter uterine environment to prevent nidation
51
Q

Advantages of mirena

A
  • Uses natural hormone at much lower dose than by other routes
  • Don’t need to take/admin daily
  • No estrogens
  • T-shaped device for comfort, safety and retention - minimal mechanically - induce irritation
  • Hormonal action confined to uterus
52
Q

Eicosanoid hormones

A
  • Prostaglandin E2 (prostin E2, dinoprostone)
  • Vaginal gel
  • Vaginal pessary/tablet (propess)
53
Q

Duration of PGE2 release

A
  • PGE2 released over 12 hours, local action to ripen cervix
54
Q

What is PGE2 indicated for

A
  • Indicated for the initiation and/or continuation of cervical ripening at or near term when need to induce birth.

Year 2 - T2 Theme 1 (20 decks)

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